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Valentina Tozzini

Publications and source records attributed to Valentina Tozzini.

7 recordsLinked to original sources
PubMed2006

Flap opening dynamics in HIV-1 protease explored with a coarse-grained model.

We present a one-bead coarse-grained model that enables dynamical simulations of proteins on the time scale of tens of microseconds. The parameterization of the force field includes accurate conformational terms that allow for fast and reliable exploration of the configurational space. The model is applied to the dynamics of flap opening in HIV-1 protease. The experimental structure of the recently crystallized semi-open conformation of HIV-1 protease is well reproduced in the simulation, which supports the accuracy of our model. Thanks to very long simulations and extensive sampling of opening and closing events, we also investigate the thermodynamics and kinetics of the opening process. We have shown that the effect of the solvent slows down the dynamics to the experimentally observed time scales. The model is found to be reliable for application to substrate docking simulations, which are currently in progress.

HIV Protease↗
PubMed2006

The chromophore of asFP595: a theoretical study.

We investigate the electronic and structural properties of the chromophore of the asCP/asFP595, a newly discovered protein of the (green) fluorescent protein family. The use of theoretical methods with different degrees of accuracy and efficiency (DFT, TDDFT, CASSCF and perturbative corrections) allows us to compare the properties of a large number of hypothetic molecular models for the chromophore. The models are sorted on the basis of the relative stability and through a comparison with the experimental values of the excitation energy. Our study indicates that the most probable structure of the photoactive moiety in the protein and in water is the one resulting from the GFP-like rather than the "alternative" cyclization scheme.

Electrons↗
PubMed2006

The influence of macromolecular crowding on HIV-1 protease internal dynamics.

High macromolecular concentrations, or crowded conditions, have been shown to affect a wide variety of molecular processes, including diffusion, association and dissociation, and protein folding and stability. Here, we model the effect of macromolecular crowding on the internal dynamics of a protein, HIV-1 protease, using Brownian dynamics simulations. HIV-1 protease possesses a pair of flaps which are postulated to open in the early stages of its catalytic mechanism. Compared to low concentrations, close-packed concentrations of repulsive crowding agents are found to significantly reduce the fraction of time that the protease flaps are open. Macromolecular crowding is likely to have a major effect on in vivo enzyme activity, and may play an important regulatory role in the viral life cycle.

Amino Acids↗
PubMed2006

Gated binding of ligands to HIV-1 protease: Brownian dynamics simulations in a coarse-grained model.

The internal motions of proteins may serve as a "gate" in some systems, which controls ligand-protein association. This study applies Brownian dynamics simulations in a coarse-grained model to study the gated association rate constants of HIV-1 proteases and drugs. The computed gated association rate constants of three protease mutants, G48V/V82A/I84V/L90M, G48V, and L90M with three drugs, amprenavir, indinavir, and saquinavir, yield good agreements with experiments. The work shows that the flap dynamics leads to "slow gating". The simulations suggest that the flap flexibility and the opening frequency of the wild-type, the G48V and L90M mutants are similar, but the flaps of the variant G48V/V82A/I84V/L90M open less frequently, resulting in a lower gated rate constant. The developed methodology is fast and provides an efficient way to predict the gated association rate constants for various protease mutants and ligands.

Carbamates↗
PubMed2005

Exploring global motions and correlations in the ribosome.

We studied slower global coupled motions of the ribosome with half a microsecond of coarse-grained molecular dynamics. A low-resolution anharmonic network model that allows for the evolution of tertiary structure and long-scale sampling was developed and parameterized. Most importantly, we find that functionally important movements of L7/L12 and L1 lateral stalks are anticorrelated. Other principal directions of motions include widening of the tRNA cleft and the rotation of the small subunit which occurs as one block and is in phase with the movement of L1 stalk. The effect of the dynamical correlation pattern on the elongation process is discussed. Small fluctuations of the 3' tRNA termini and anticodon nucleotides show tight alignment of substrates for the reaction. Our model provides an efficient and reliable way to study the dynamics of large biomolecular systems composed of both proteins and nucleic acids.

Anticodon↗
PubMed2005

Coarse-grained models for proteins.

Coarse-grained models for proteins and biomolecular aggregates have recently enjoyed renewed interest. Coarse-grained representations combined with enhanced computer power currently allow the simulation of systems of biologically relevant size (submicrometric) and timescale (microsecond or millisecond). Although these techniques still cannot be considered as predictive as all-atom simulations, noticeable advances have recently been achieved, mainly concerning the use of more rigorous parameterization techniques and novel algorithms for sampling configurational space. Moreover, the simulation size scales and timescales coincide with those that can be reached with the most advanced spectroscopic techniques, making it possible to directly compare simulation and experiment.

Algorithms↗